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BRAIN&
MIND
SYMPOSIUM
OCTOBER 14 - 15, 2021
ONLINE
SYMPOSIUM
BOOKLETBRAIN&
MIND
SYMPOSIUM
Dear Symposium participant,
Welcome to the Brain & Mind Symposium 2021! This symposium is the annual scientific
event organised by the doctoral students of the Doctoral Programme Brain & Mind at
the University of Helsinki and Aalto University.
In this booklet you will find the final event programme and the short biosketches of all
the main speakers as well as the abstracts for the posters presented during the event.
We wholeheartedly welcome you to the Symposium.
Brain & Mind Student Council 2021
Lauri Elsilä
Vicky Gkini
Natali Martyniuk
David Micinski
Annika SchäferPROGRAMME
Thursday October 14th, 2021
09.45 – 10.00 Opening words by Lauri Parkkonen
10.00 – 12.00 Symposium: Learning and Memory
Gisella Vetere: “Decoding memory formation and stabilization in mice”
Athena Akrami: “The lingering past in working memory — from sensory
history to optimal learning of temporal regularities”
13.00 – 14.00 Poster presentations
14.15 – 16.15 Symposium: Pain and nociception
Ewan St. John Smith: “Naked Nociception: Tales from the naked mole-
rat”
Katrin Schrenk-Siemens: “Human stem cell derived neurons: a step
towards translational pain research?”
16.30 – 18.00 Newly established group leaders in Helsinki
Teppo Särkämö (University of Helsinki)
Henrike Hartung (University of Helsinki)
Coralie Di Scala (University of Helsinki)
Yoni Levy (Aalto University)
Olli Pietilä (University of Helsinki)
Teemu Aitta-aho (University of Helsinki)
Tom McWilliams (University of Helsinki)
18.45 – 00.00 Dinner at GLO Hotel Art
All times in Helsinki time (EEST, UTC+3)PROGRAMME
Friday October 15th, 2021
9.45 – 12.45 Symposium: Regulation of motivation & emotions
Ewelina Knapska: “Second-hand emotions. What can rodents learn
about the world from other’s bliss and fear?”
Angela Roberts: “Prefrontal regulation of positive and negative emotions
in a primate”
Roshan Cools: “Chemistry of the adaptive mind: lessons from dopamine”
13.45 – 14.45 Workshop: Climate and environment crisis in neuroscience
Kate Jeffery
Commentary by UH vice-rector Tom Böhling
15.00 – 16.00 Poster presentations
16.15 – 18.15 Symposium: Glial cells
David Attwell: “The role of glia and pericytes in regulating brain blood
flow in health and disease”
Benedikt Berninger: “Engineering new interneurons in the cerebral
cortex in vivo”
18.15 Closing words by Iiris Hovatta
All times in Helsinki time (EEST, UTC+3)SYMPOSIA SPEAKERS Gisella Vetere “Decoding memory formation and stabilization in mice” Gisella Vetere is a Professor in Neurobiology and the team leader of the C4 group (Cerebral codes and circuits connectivity) at the ESPCI in Paris since August 2018. Her training is in behavioural, cellular and systems neuroscience, with a specific focus on learning and memory. She did her PhD in Rome (Italy) where she studied synaptic plasticity changes that occur following acquisition of new and long-lasting memories. In 2014 she moved to Canada to work at the Sick Children Hospital in the laboratory of Dr. Paul Frankland. She established the role of structural and functional synaptic changes in the process of memory consolidation. She also artificially engineered specific neurons to create a memory without real experience. She was awarded several prizes and grant for her research including the ANR JCJC, ATIP/Avenir, NARSAD Yonge Investigators, Aspirational Neuroscience Prize and the Brain Star Award. Athena Akrami “The lingering past in working memory — from sensory history to optimal learning of temporal regularities” Athena joined the faculty at Sainsbury Wellcome Centre (SWC), UCL, in November 2018. She obtained her BA in Biomedical Engineering from Tehran Polytechnic (Amirkabir University of Technology) and her PhD in Computational Neuroscience from International School for Advanced Studies (SISSA), with Alessandro Treves. She then became a postdoctoral fellow at SISSA where she switched gears towards experimental neuroscience with Mathew Diamond, and then at Princeton University where she was a Howard Hughes Medical Institute fellow and worked with Carlos Brody on Parametric Working Memory. Her Learning, Inference & Memory laboratory at SWC, is focused on understanding the fundamental principles of statistical learning – the ability of the brain to discover and exploit relevant regularities and structures in the world in an unsupervised manner. In all of her research programs, experiments are intertwined with hypotheses drawn from theoretical investigations and computational modelings. Since April 2020, Athena has also become an accidental advocate and researcher of Long COVID.
SYMPOSIA SPEAKERS Ewan St. John Smith “Naked Nociception: Tales From The Naked Mole-Rat” Ewan completed his undergraduate degree in pharmacology at the University of Bath, followed by a PhD with Peter McNaughton at the University of Cambridge working on acid-sensing ion channels. He then moved to work with Gary Lewin at the Max-Delbrück Centre in Berlin as an Alexander von Humboldt Research Fellow, where he began working on pain peculiarities of the naked mole-rat. This was followed by a 1-year stint with Niels Ringstad at the Skirball Institute of Biomolecular Medicine at NYU as a Max Kade Foundation Fellow, where he worked on CO2-sensing in C. elegans. In 2013 he was appointed to a Lectureship in Pharmacology at the University of Cambridge where his research group focuses on understanding the molecular basis of nociception using both mice and naked mole-rats as model systems, as well as investigating the cancer resistance and healthy ageing of naked mole-rats. He was promoted to Senior Lecturer in 2017 and Reader in 2019, also being a Fellow of Corpus Christi College where he is Director of Studies in Biological Natural Sciences. Work in the Smith lab is funded by the BBSRC, MRC, Versus Arthritis, Dunhill Medical Trust, Astra Zeneca, Beiersdorf and GSK. Katrin Schrenk-Siemens “Human stem cell derived neurons: a step towards translational pain research?” Katrin has been working with human embryonic stem cells for 20 years, with an emphasis on the generation of central and peripheral neurons. She studied Biology, received her PhD in the field of neuroscience from the University of Basel, Switzerland and worked with adult stem cells during her first postdoc at Stanford University. She then started to focus on the development of differentiation procedures to generate sensory neurons during her second postdoc in Berlin. Currently Katrin is located at the Institute of Pharmacology at Heidelberg University and a co-PI in the Heidelberg pain consortium (SFB1158). Her main interest is the development of an in vitro model system using human pluripotent stem cell-derived nociceptors and glutamatergic neurons as a novel tool to investigate synaptic transmission in models of sensitization or pain-related mutations.
SYMPOSIA SPEAKERS Ewelina Knapska “Second-hand emotions. What can rodents learn about the world from other’s bliss and fear?” Born in Poland in 1977, Ewelina Knapska obtained MSc degrees in biology and psychology from the University of Warsaw. In 2001 she started working with Tomasz Werka and Leszek Kaczmarek, studying the heterogeneity of the amygdala in control of positive and negative emotions. After obtaining her Ph.D. from the Nencki Institute of Experimental Biology PAS in 2006, Ewelina moved to Ann Arbor, USA, for a postdoc in the laboratory of Prof. Stephen Maren at the University of Michigan. She moved back to Poland in 2008, getting a stipend from the Foundation for Polish Science and becoming an assistant professor at the Nencki Institute of Experimental Biology PAS. In 2012, she obtained habilitation (DSc) and became an associate professor and the head of the newly created Laboratory of Neurobiology of Emotions. In 2016 she received a Starting Grant from the European Research Council to study the amygdala's role in controlling socially transferred emotions. Since 2018 she has been Vice-President of the Centre of Excellence for Neural Plasticity and Brain Disorders (BRAINCITY) in the Nencki Institute of Experimental Biology. Angela Roberts “Prefrontal regulation of positive and negative emotions in a primate” Angela Roberts obtained her PhD in neuroendocrinology from University of Cambridge (1985) and following postdoctoral studies researching into the neural and neurochemical basis of cognitive flexibility was appointed Lecturer in Department of Anatomy, Cambridge, in 1996, becoming Professor of Behavioural Neuroscience in 2010. She was elected a Fellow of the Academy of Medical Sciences in 2016. Recent scientific contributions have involved establishing non-human primate models of positive and negative emotion regulation, fractionating out the distinct prefrontal networks that may underlie the varied aetiology of affective disorders and elucidating the sensitivity of these networks to anxiolytics/antidepressants essential for the more effective targeting of current pharmacotherapies. She received the Goldman-Rakic Prize for outstanding achievements in Cognitive Neuroscience in 2020.
SYMPOSIA SPEAKERS Roshan Cools "Chemistry of the adaptive mind: lessons from dopamine" Roshan Cools has made lasting contributions to cognitive neuroscience, providing empirical foundations of current theories of dopamine and serotonin’s roles in human motivational and cognitive control. She has pioneered the combination of advanced techniques, including pharmacological fMRI, chemical PET, psychopharmacology and computational cognitive science. She is an elected member of the Royal Netherlands Academy of Arts and Sciences and the Academia Europaea. She is also an active member of the Advisory Council for Science, Technology and Innovation (to the Dutch government). After completing her undergraduate degree in Experimental Psychology at the University of Groningen in 1998, she moved to Trevor Robbins’ lab at the University of Cambridge, UK, for a PhD degree (2002), Royal Society Research Fellowships until 2007. She also spent two visiting post-doc years at UC Berkeley working with Mark D’Esposito from 2003. In November 2007 she returned to The Netherlands, where she is Principal Investigator at the Donders Institute for Brain, Cognition and Behaviour and full Professor of Cognitive Neuropsychiatry at the Radboud university medical center in Nijmegen, running a productive group of international researchers studying the chemical neuromodulation of human cognition (www.roshancools.com). Kate Jeffery Workshop on the climate crisis Kate Jeffery is a behavioural neuroscientist at University College London. Her scientific research explores how the brain makes an internal map of space for use in navigation and memory. At UCL she heads the Institute of Behavioural Neuroscience in the Division of Psychology and Language Sciences, and is Vice Dean (Research) for the Faculty of Brain Sciences. She is also co- director of the electrophysiology company Axona Ltd, which makes high- density recording systems for behavioural neuroscientists, and is a Fellow of the Royal Society of Biology and Fellow of the Royal Institute of Navigation, where she chairs the Cognitive Navigation Special Interest group. She is interested in enhancing public understanding of science and in this role, has given many talks not only about her research but also about the climate crisis.
SYMPOSIA SPEAKERS David Attwell “The role of glia and pericytes in regulating brain blood flow in health and disease” David Attwell did a first degree in physics and a PhD on the electrophysiology of nerve and muscle cells with Julian Jack in Oxford, before spending 2 years in Berkeley studying the retina with Frank Werblin. On returning to the UK, he moved to the Department of Physiology at University College London, where he has remained ever since. He has worked on a wide range of subjects including the properties of glial cells, glutamate transporters, stroke, the formation of myelin by oligodendrocytes, how neuronal computation is powered and the control of cerebral blood flow. He was made a Fellow of the Royal Society in 2001. Benedikt Berninger “Engineering new interneurons in the cerebral cortex in vivo” Benedikt studied biology at the University of Munich. After a PhD on activity- dependent neurotrophin regulation in the laboratory of Hans Thoenen, he joined Mu-ming Poo's lab at the University of California San Diego to investigate rapid action of neurotrophins at synapses and growth cones. Following his return to Munich he got fascinated by adult neural stem cells and the neurogenic fate potential of glia. Working with Magdalena Götz at the Stem Cell Institute, Helmholtz Zentrum München and the University of Munich, he discovered the proneural factors Neurog2 and Ascl1 as key reprogramming factors for glia-to-neuron conversion. In 2012 he was appointed professor of Physiological Chemistry at the University Medical Center Mainz and in 2018 he became Professor for Developmental Neurobiology at King's College London. Since 2021, Benedikt leads also a satellite group at the Francis Crick Institute. His research covers a broad range of topics from molecular mechanisms of neuronal reprogramming to circuit remodelling.
NEWLY ESTABLISHED GROUP LEADERS Teppo Särkämö Teppo Särkämö is an Associate Professor of Neuropsychology at the Department of Psychology and Logopedics, University of Helsinki and the Group leader of the Music, Ageing and Rehabilitation Team (MART) at the Cognitive Brain Research Unit (CBRU). His research focuses on the psychological and neural mechanisms of language and music and their neurological deficits (aphasia and amusia) and on the effects of musical activities and music-based rehabilitation methods in ageing and in different neurological illnesses. Currently, he leads a large ERC- funded project on singing in normal ageing and aphasia and on music-evoked memories in Alzheimer’s disease. Henrike Hartung Henrike Hartung is an Academy of Finland Research Fellow and associated group leader at the Neuroscience Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki. Her main research interest is on the developmental origin of neuropsychiatric disorders. With her team, she investigates the role of early-life stress, including birth stress, on the functional development of the brain with a focus on the serotonergic system and prefrontal-amygdala networks. Her experimental approach mainly includes in vivo state-of-the-art electrophysiological recording techniques in developing rodents in combination with anatomical, pharmacological and behavioural methods. Coralie Di Scala Coralie Di Scala got a PhD from Aix-Marseille University (France) in Molecular Neurosciences (supervised by Prof. Fantini and Dr. Chahinian). She discovered a new mechanism of beta-amyloid peptide toxicity within the membrane of cells. In 2018, she joined the Rivera lab (INSERM, France) and focused on stability of membrane proteins within the membrane in a context of epilepsy. In 2019, she won the prize Valérie Chamaillard from the Fondation de France that rewards the best young researcher project on epilepsy in France. In 2020, she started her group at Neuroscience Center as Academy Fellow. Her team deciphers the molecular mechanisms underlying lipid-protein interactions and evaluates their functional impacts for nervous system diseases with an emphasis on epilepsy. Yoni Levy Yoni (Jonathan) Levy is a social neuroscientist at Aalto University and in IDC Herzliya. What drives his work in science is the passion to investigate phenomena from multiple perspectives, and merging them into novel representations. In this brief talk he will present his neuroscientific work on timely social phenomena.
NEWLY ESTABLISHED GROUP LEADERS Olli Pietiläinen Olli Pietiläinen, Ph.D., is a group leader at the HiLIFE Neuroscience Center (NC) at the University of Helsinki and a researcher at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard. His group in NC focuses on using genomic approaches in iPSC derived neuronal models to study psychiatric disorders. Olli graduated as Ph.D. from the Institute for Molecular Medicine Finland (supervised by Prof. Aarno Palotie & Academician Leena Palotie). Before joining NC, Olli worked with Professor Kevin Eggan at Harvard University. His work there focused on genomic modeling of genetic risk variants in schizophrenia in iPSC derived neuronal models. Teemu Aitta-aho Teemu Aitta-aho is currently a group leader and a lecturer teaching pharmacology and neuroscience at the University of Helsinki, Finland. He studied pharmacy and pharmacology at the Universities of Helsinki and Gothenburg, completed PhD on drug-induced neuroplasticity in 2012, and received postdoctoral training in 2014-2016 in the University of Cambridge. Currently he is interested in neurochemically-defined neurocircuitries in food intake and related motivated behaviours. To understand these, he is using novel cell-type specific artificial receptor-ligand systems and light-guided neural control with optogenetics, as well as brain cell imaging in freely moving animals. Tom McWilliams Tom McWilliams has a multidisciplinary training background with expertise in developmental and degeneration neuroscience. He trained with Alun M. Davies and Stephen B. Dunnett on the Wellcome Trust Four-Year PhD Programme in Integrative Neuroscience at Cardiff University, UK. Here, Tom discovered new mechanisms controlling neural circuit formation in the mammalian CNS and PNS. Subsequently, at the MRC Protein Phosphorylation & Ubiquitylation Unit, he led several studies that revealed groundbreaking insights into the regulation of physiological mitophagy across multiple organ systems, with significant relevance for neural integrity. In 2018, he was recruited to the University of Helsinki and appointed Tenure-Track Assistant Professor of Mitochodrial Medicine. In 2021, Tom was elected a Scholar of the FENS-Kavli Network of Excellence. The McWilliams lab deciphers the metabolic and mechanistic regulation of autophagy in tissue development, degeneration, and repair.
POSTERS
Posters will be presented on Slack platform on both days. The presentations have been divided
more or less in two, with always a half of the presenters available on one day; these days are listed
below. If the presenter is available on both days, they have implicated so on their poster channel.
Here you can find the list of poster presenters, their poster/channel number and the day of
presentation. The provided titles and abstracts can be found on the following pages.
Poster No Presenter name Institution Presentation day
1 Adrien Gigliotta University of Helsinki Thursday
2 Amirreza Asayesh University of Helsinki Friday
3 Cecilia Cannarozzo University of Helsinki Friday
4 Marta Saez Garcia Neuroscience Center Friday
5 Nikhil Singh Yenepoya Research Centre Thursday
6 Milo Grotell University of Helsinki Thursday
7 Saeed Montazeri Moghadam University of Helsinki Friday
8 Pushpa Khanal University of Helsinki/Minerva Thursday
9 Alessia Gallucci University of Milano-Bicocca Thursday
10 Emmi Pentikäinen University of Helsinki Friday
11 Ying Chieh Wu University of Helsinki Thursday
12 Anna Ptukha University of Helsinki Friday
13 Julius Rönkkö University of Helsinki Thursday
14 Jussi Tiihonen University of Helsinki Thursday
15 Ceren Pajanoja University of Helsinki Friday
16 Pilar Cerveró Universidad de Salamanca Friday
17 Raquel Flores INCYL, USAL Thursday
18 Andrea Álvarez Vázquez University of Salamanca Thursday
19 Adriana Della Pietra University of Eastern Finland Friday
20 Alex Subias Gusils Autonomous University of Barcelona Friday
21 Ilja Salakka University of Helsinki Thursday
22 Adam Alvarez Autonomous University of Barcelona Thursday
23 Daniel Garton University of Helsinki Friday
24 Tommi Aho University of Helsinki Friday
25 Viola Helaakoski University of Helsinki Thursday
26 Jonatan Panula University of Helsinki Friday
27 Carla Filipa Simões Henriques Instituto Gulbenkian de Ciência ThursdayPOSTERS 1 Genetic background modulates the effect of chronic psychosocial stress on microglial function Adrien Gigliotta, Federica Cafaro, Mikaela Laine , Kalevi Trontti and Iiris Hovatta SleepWell Research Program and Department of Psychology and Logopedics, Faculty of Medicine; and Neuroscience Center, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Finland Anxiety disorders are the most prevalent psychiatric disorders and chronic psychosocial stress significantly contributes to their onset. Using the mouse chronic social defeat stress model (CSDS), our group recently identified myelin plasticity as a substantial response to stress, which varied across brain regions, and was genetically controlled. Critically, changes in myelin thickness varied between stress resilient (mice that did not develop social avoidance after CSDS) and susceptible (mice that developed social avoidance after CSDS) animals. Microglia are activated by chronic psychosocial stress and their activation and morphological modifications have been suggested to contribute to the development of anxiety-like states. We hypothesized that microglia-OPCs crosstalk is involved in the regulation of myelin plasticity and in resilience and susceptibility to psychosocial stress. Using an immunohistochemical approach in the anterior cingulate cortex, we compared the number of activated microglia (CD68+/IBA1+ cells) and the number of microglia engulfing OPCs (PDGFRa+ /IBA1+ cells) between C57BL/6NCrl (B6; innately non-anxious and mostly stress resilient) and DBA/2NCrl (D2; innately anxious and mostly stress susceptible) mice after CSDS. While CSDS did not affect the number of activated microglia, the area of CD68+ lysosomes was larger in B6 susceptible animals compared to controls, suggesting microglial activation after CSDS. We observed a smaller number of microglia engulfing OPCs and a longer distance between OPCs and the closest microglia in D2 susceptible animals compared to controls, indicating fewer microglia-OPC interactions. Our RNA-sequencing data from the medial prefrontal cortex after CSDS indicate that differentially expressed genes associated with microglia activation and phagocytosis are overrepresented among the differentially expressed genes in B6 susceptible vs control mice. Taken together, our results suggest that chronic psychosocial stress affects microglial function and that the effects are different in resilient and susceptible animals and in different mouse strains, highlighting the importance of considering the genetic background in the study of stress- induced activation of microglia.
POSTERS 2 Developing a disposable aEEG cap for NICU Amirreza Asayesh, Sampsa Vanhatalo, Elina Ilen Department of Neuroscience, Faulty of Medicine, University of Helsinki; and Department of Desgin, School of Arts, Design and Architecture, Aalto University Background and Purpose: Long-term EEG monitoring is quite challenging with current EEG setups. Challenges Intensificate while aEEG recording from newborn infants at NICU as skin preparation by abrading or puncturing the stratum corneum and obstacles of multiple checkups of the skin-electrode interface for a stable signal quality in the long-term recordings. Materials and Methodology:A table of the requirements for an ideal cap, electrode, skin-electrode interface, and user experience was listed and described based on the needs for long-term aEEG recording from the newborn infants at NICU. We compared novel materials as conductive textiles (textured and woven), conductive velcro, sponge, super absorbent hydrogel (SAP), and thick-layer and thin-layer hydrofiber (HF) to conventional skin-electrode interfaces; as electro gel, tensive gel, conductive cream, and conductive paste to analyze each material’s performance. Furthermore, comparing the connection stability between the AgCl electrode and the skin surface in the long-term recording. Then we compared the materials in a solution dehydration test to clarify the electrodes’ ability to store conductive solutions for extended periods in open space and incubator mimicking space. The performance of chosen materials (Sponge, SAH, HF, and Sticker electrode) from the evaporation study compared on an armband sleeve for long- term biosignal recording on an unprepared skin. Then The performance of HF as the final material compared to a sticker electrode impregnated with tensive gel (to make it stable for long-time recordings) on a headband while recording biosignals from the forehead and impedance measurement. Results: According to the electrode requirements, conductive textiles had poor performance in absorbing and storing conductive solutions. Also, conductive velcros had rigid coated surfaces that could irritate the infant’s skin. SAP and HF had similar outcomes in the Solution dehydration test, and they remained almost 75% after 6 hours and 20% hydration after 24 hours in an incubator mimicking environment. The sponge material was dehydrated completely before 12 hours of recording. The SAH material had a fragile structure and higher powerline (50hz) amplitude RMS component after 12 hours of recording. The electrical impedance for HF was significantly lower than tensive gel impregnated sticker electrode on an unprepared forehead skin, and the impedance remained under 15kΩ in 10Hz frequency for 18 hours after the recording started.
POSTERS 3 Ketamine reinstates visual plasticity in adult mice in a dose- independent manner Cannarozzo C, Steinzeig A, Casarotto PC, Castrén E. University of Helsinki,Neuroscience Center HILIFE, Helsinki, Finland The ocular dominance plasticity (ODP) in the visual cortex is an established model to study activity-dependent plasticity: the forced closure of one eye (monocular deprivation) causes a shift in ocular dominance. Chronic treatment with fluoxetine, a classical antidepressant, has been shown to induce a state of juvenile-like plasticity in the adult mouse visual cortex, which was previously thought to be restricted only to a brief postnatal period. Since classical antidepressants take several weeks before their beneficial effects appear, research has been focusing on finding solutions to induce ODP in shorter latency. Ketamine has been described as a rapid-acting antidepressant in many preclinical and clinical trials, and the underlying mechanism is still under debate. Recently, we have reported that ketamine and its active metabolite 2R,6R-Hydroxynorketamine (R,R-HNK, both at 10 mg/kg) reinstate visual cortex plasticity in the adult mouse, with ketamine showing a weaker ocular dominance shift than R,R-HNK and fluoxetine. To assess whether this could be explained by the dose used, here we tested a higher or lower dose (20 or 3 mg/kg) of ketamine and the same dose of R,RHNK administered three times, every two days, during one week of monocular deprivation. Notably, these different doses resulted in comparable shifts in ocular dominance, yet still weaker than the ones obtained with R,R-HNK or fluoxetine, therefore suggesting a dose-independent mechanism for ketamine-induced ODP.
POSTERS 5 Development and Functional Characterisation of an in-vitro model of Ischemic Stroke Nikhil Singh, Arnab Datta Yenepoya Research Center, Mangalore, India Background: Ischemic stroke is one of the major causes of death and disability worldwide with limited treatment options. There is an urgent need to develop effective and cheaper therapies. An in-vitro model is a useful tool for basic and pre-clinical research on ischemic stroke. These models are used to understand the cell-type-specific mechanisms and signalling. Objective: The primary objective was to establish hypoxia (HYP) and oxygen- glucose deprivation (OGD) model using cultured brain cells of neuronal and glial origin and subsequent estimation of the morphological and metabolic damage in a time-dependent manner. Methods: Cultured neuron (Neuro-2A, N2a) and astrocyte (CTX-TNA2) cells were exposed to variable durations of HYP and OGD spanning from 4 to 24 h to cover the acute and subacute phases of ischemic injury. A dissolved oxygen meter was used to confirm the persistent reduction of oxygen levels below 2% during OGD. Serum deprivation and retinoic acid treatment was used to induce differentiation of culture brain cells. Trypan blue and simple inverted microscopy were used to determine cell death and any change in cellular morphology. MTT assay was used to determine metabolic activity of the cells following HYP and OGD. Results: Forty-eight hr of serum deprivation was used to induce cellular differentiation. During early phases (4-8hr) of OGD and hypoxic injury, the relative metabolic activity of undifferentiated and differentiated neurons compared to control neurons was equal to or higher than the astrocytes. Variable changes in the metabolic activity of differentiated astrocytes were observed between 8hr and 16hr of hypoxic injury, while the metabolic activity of the neurons was reducing consistently with an increase in the duration of injury. Clearly, neurons and astrocytes responded differently to identical durations of hypoxic and ischemic stress. Conclusion: An in vitro OGD model has been established using cultured brain cells and validated using an MTT assay. This model can be used for mechanistic studies or for testing the cerebro-protective efficacy of novel chemical or biological entities.
POSTERS 6 Conditioned Reward of Opioids is Impaired in GABA-A Receptor δ Subunit Knockout Milo Grotell, Elena de Miguel, Juho Aaltio, Aino K. Manner, Mikko Vahermo, Jari Yli-Kauhaluoma, Anni-Maija Linden, Teemu Aitta-aho, Esa R. Korpi Department of Pharmacology, Faculty of Medicine; and Drug Discovery Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian brain. In the brain, GABA affects multiple different GABA-receptors. These receptors can be divided into ionotropic and metabotropic classes. The ionotropic effects are mainly mediated via A-type GABA receptors (GABAARs). Furthermore, GABAARs are mainly expressed in the synapses. However, there are also extrasynaptically expressed subpopulations of those receptors, which often contain delta-subunit.Interestingly delta- subunit GABAARs (d-GABAARs) are expressed in multiple locations needed for reward and populated with opioid receptors. Due to the lack of a specific d-GABAAR antagonist, a transgenic mouse model genetically lacking the d-GABAARs is used instead (d-KO). As opioids, like morphine, are known to be highly rewarding and are known to produce addiction, we wanted to evaluate if d-GABAAR-modulation could play a role in reward production. We used the conditioned place preference paradigm to evaluate if the morphine-induced reward is altered in d-KO mice compared to their littermates. We observed that d-KO mice did not produce conditioned place preference, whereas their littermates did. Our finding suggests that d-GABAAR-mediated modulation is crucial for normal reward. The underlining mechanism remains debatable, but it could be that d- GABAAR-mediated autoinhibition counteracts opioid-produced inhibition of GABAergic interneurons.
POSTERS 7 Building an Open Source Classifier for the Neonatal EEG Background Moghadam, S.M. (1), Pinchefsky, E. (2), Tse, I. (1), Marchi, V. (1,3), Kohonen, J. (4), Kauppila, M. (1), Airaksinen, M. (1,5), Tapani, K. (1), Nevalainen, P. (1), Hahn, C. (6), Tam, E.W. (6), Stevenson, N.J. (7), and Vanhatalo, S. (1,8). 1 BABA Center, Pediatric Research Centre, Department of Clinical Neurophysiology, Children’s Hospital and HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland, 2 Division of Neurology, Department of Paediatrics, Sainte-Justine University Hospital Centre, University of Montreal, Montreal, QC, Canada, 3 Department of Developmental Neuroscience, Stella Maris Scientific Institute, IRCCS Fondazione Stella Maris Foundation, Pisa, Italy, 4 Department of Computer Science, Aalto University, Espoo, Finland, 5 Department of Signal Processing and Acoustics, Aalto University, Espoo, Finland, 6 Department of Paediatrics (Neurology), The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada, 7 Brain Modelling Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia, 8 Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland Neonatal brain monitoring in the neonatal intensive care units (NICU) requires a continuous review of the spontaneous cortical activity, i.e., the electroencephalograph (EEG) background activity. This needs development of bedside methods for an automated assessment of the EEG background activity. We present development of the key components of a neonatal EEG background classifier, starting from the visual background scoring to classifier design, and finally to possible bedside visualization of the classifier results. A dataset with 13,200 5-minute EEG epochs (8–16 channels) from 27 infants with birth asphyxia was used for classifier training after scoring by two independent experts. We tested three classifier designs based on 98 computational features, and their performance was assessed with respect to scoring system, pre- and post-processing of labels and outputs, choice of channels, and visualization in monitor displays. The optimal solution achieved an overall classification accuracy of 97% with a range across subjects of 81–100%. Our results showed that an automated bedside classifier of EEG background is achievable.
POSTERS 8 GAS7 initiates new dendritic spines in activation-dependent manner Pushpa Khanal (1,2), Zoran Boskovic (3), Aruna Ghimire (1), Patricio Opazo (3), Pirta Hotulainen (1) 1 Minerva Foundation Institute for Medical Research, Helsinki, Finland 2 HiLIFE-Neuroscience Center, University of Helsinki, Helsinki, Finland 3 Clem Jones Centre for Ageing Dementia Research, The Queensland Brain Institute, The University of Queensland, Brisbane, Australia Dendritic spines are small membrane-protrusions along neuronal dendrites and are the major postsynaptic target of excitatory synapses. They are highly dynamic structures whose shape, size, and number change throughout development as well as in response to the pattern and strength of synaptic activity. The actin cytoskeleton is known to have an important role in the morphogenesis and structural remodeling of dendritic spines. However, the exact mechanism of dendritic spine initiation is largely unknown. In this study we tested a selection of BAR domain containing proteins and identified GAS7 as a novel dendritic spine initiation factor. Overexpression of GAS7 in rat hippocampal neuronal cultures increased the dendritic spine density whereas the shRNA knock-down of GAS7 significantly decreased the spine density. Studies in rat hippocampal neuronal cultures and organotypic hippocampal slices indicate that GAS7 is localized to dendritic spines as well as to patches on the dendritic shaft plasma membrane. Live cell time-lapse imaging showed that the localization of these patches correlates with new spine formation. Moreover, treatment of organotypic hippocampal slices with bicuculline (GABAA receptors antagonist) leads to enrichment of the localization of GAS7 to the dendritic shaft patches. These results suggest that GAS7 is a novel dendritic spine initiation factor that can induce the formation of new spines in an activity-dependent manner.
POSTERS 9 Combining tDCS and CRT for the treatment of eating disorders patients Gallucci, A.(1,2), Bergamelli, E. (3), Bertelli, S. (4), D’Agostino, A. (3,4), Mattavelli, G. (5), Gambini O. (3,4,6), Romero Lauro, L.J. (2,7) 1 Ph.D. program in Neuroscience, School of Medicine and Surgery, University of Milano- Bicocca, Monza, Italy. 2 NeuroMi (Neuroscience Center), University of Milano-Bicocca, Italy 3 Department of Health Sciences, University of Milan, Milan, Italy 4 Department of Mental Health, ASST Santi Paolo e Carlo, Milan, Italy 5 School of Advanced Studies, IUSS, Pavia, Italy 6 CRC “Aldo Ravelli” for Neurotechnology and Experimental Brain Therapeutics, University of Milan Medical School, Milan, Italy 7Department of Psychology, University of Milano-Bicocca, Milan, Italy Objective. Cognitive Remediation Therapy (CRT) significantly improves set-shifting and central coherence in patients suffering from Anorexia Nervosa (AN) or Bulimia Nervosa (BN). Evidence suggested that the left dorsolateral prefrontal cortex (lDLPFC) might be crucially involved in the neurobiological mechanisms underlying ED’s cognitive symptoms. Thus, combining CRT with the Transcranial Direct Current Stimulation (tDCS), despite still unexplored, could represent a promising method to boost therapeutic interventions. Method. Seven patients with AN and five with BN were randomly assigned to receive anodal or sham tDCS over the lDLPFC while performing 3 weeks- CRT intervention. Neuropsychological and clinical evaluations were performed to assess patients’ cognitive skills and core symptoms at baseline and immediately after the combined treatment. Results. Preliminary results showed that the drive for thinness, personal alienation, interpersonal difficulties, affective problems as well as the global psychological maladjustment subscales of the Eating Disorder Inventory-3 (EDI-3) significantly decreased at the post-treatment evaluation in both the whole sample and in the anodal subgroup, while no effects were observed in the sham group. Conclusion. Our exploratory data suggest that the combined treatment modulated some of the clinical symptoms of patients, despite the EDI-3 results lack of consistency with the other clinical and neuropsychological tests.
POSTERS 10 Benefits of choir singing on complex auditory encoding in older adults Emmi Pentikäinen (1), Lilli Kimppa (1), Tommi Makkonen (1), Anni Pitkäniemi (1), Ilja Salakka (1), Petri Paavilainen (1), Mari Tervaniemi (1,2), Teppo Särkämö (1) 1 Cognitive Brain Research Unit, Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2 CICERO Learning Network, University of Helsinki, Helsinki, Finland Normal aging is accompanied by difficulties in hearing and auditory information processing, especially in more complex sound environments. Choir singing requires fast and efficient processing of multiple sound features and could therefore potentially mitigate the deleterious effects of aging on complex auditory encoding, but this has not been studied previously. Using electroencephalography measurements in healthy older adult (age ≥ 60 years) choir singers and control subjects, we recorded auditory event-related potentials (ERPs) in two simple oddball conditions, in which the pitch and spatial location of the sounds was varied, as well as in a complex oddball condition, which involved higher-level encoding of abstract regularities in both pitch and location information, based on an implicit rule combining these two features. We analyzed standard P1 and N1 responses and change-related mismatch negativity (MMN) responses in left, middle, and right fronto- central regions of interest (ROIs) in each condition. In the simple pitch and location conditions, the choir singers had smaller N1 responses across all ROIs compared to the control subjects, whereas the MMN responses did not differ between groups. In the complex condition, the choir singers showed a larger MMN than the controls specifically in the left ROI, which also correlated with better executive functioning measured with a verbal fluency test. These results suggest that regular choir singing is associated both with more e
POSTERS 11 iPCS-derived APPswe mutant pericytes produce beta-amyloid and induce the activatation of co-cultured astrocytes Ying-Chieh Wu (1), Taisia Rolova (1), Šárka Lehtonen (1,2) and Jari Koistinaho (1,2) 1 Neuroscience Center; University of Helsinki; Helsinki; Finland. 2 A.I.Virtanen Institute for Molecular Sciences; University of Eastern Finland; Kuopio; Finland. Cerebrovascular dysfunction has been reported in Alzheimer's disease (AD) brains, but its underlying mechanism remains unclear. Cerebral amyloid angiopathy (CAA) is a form of vascular dysfunction caused by beta-amyloid (Aβ) accumulation in brain vessel walls. CAA is present in nearly 90 percent of AD patients suggesting it could be the primary pathology for vascular dysfunction in AD. The blood vessels in the brain possess unique properties, termed blood-brain barrier (BBB), composed of endothelial cells, pericytes, and astrocyte endfeets. Pericytes wrapping around endothelial cells are crucial for vasculature stabilization. Substantial pericyte loss has been reported in AD correlating with the BBB breakdown. We wonder if pericytes play a role in AD-associated vascular dysfunction and CAA pathology. To address these questions, we generated iPSC-derived pericytes from patients harboring APP Swedish mutation (KM670/671NL) and investigated the underlying mechanisms.
POSTERS 12 Eye movements as a potential strategy for fine stereoacuity Anna Ptukha (1,2,3) 1.Doctoral Programme Brain & Mind 2.Cognitive Brain Research Unit 3.High Performance Cognition group University of Helsinki Perceived positions of stationary objects in the three-dimensional (3D) space and distances between them are stable according to everyday experience. Meanwhile, eyes, head and body move constantly, and the two-dimensional (2D) projections of the visual scene on the retinas undergo ongoing changes. Even during one precise fixation, so- called fixational eye movements (FEMs) occur a few times per second. Time period between consecutive FEMs is enough to perceive a 3D scene, but several FEMs usually occur in one fixation. Why then the perceived scene does not change with FEMs during fixation? The problem of deriving 3D scene from several pairs of 2D projections is ambiguous considering humans do not have precise readout of their eye positions. The assumption about stability of spatial positions of objects potentially helps to reduce the ambiguity. Binocular vision creates representation of space from differences between images projected to the retinae of two eyes. Considering that fine stereo information is lost when differences between 2D projections change after FEM, how can humans achieve high stereoacuity under FEMs? In psychophysics and eye tracking experiment, we found that a common solution is assigned to pairs of 2D projections formed from a given 3D scene during possible FEMs. We found that humans can exhibit stereoacuity higher than half of typical FEM amplitude, thus only distinct patterns of FEMs should appear, allowing high stereoacuity along only distinct directions.
POSTERS 13 Mutant calcium regulator IP3R3 in ER-mitochondria contact sites causes hereditary neuropathy Julius Rönkkö (1), Svetlana Molchanova (1,2), Yago Rodriguez (1), Mari Auranen (3), Jussi Toppila (4), Jouni Kvist (1), Anastasia Ludwig (5), Anders Paetau (6), Claudio Rivera (5,7), Henna Tyynismaa (1,5,8), Emil Ylikallio (1,3) 1 Stem Cells and Metabolism Research Program, University of Helsinki, Finland; 2 Molecular and Integrative Biosciences Research Program, University of Helsinki, Finland; 3 Clinical Neurosciences, University of Helsinki and Helsinki University Hospital, Finland; 4 Department of Clinical Neurophysiology, Medical Imaging Center, Helsinki University Central Hospital, Finland; 5 Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Finland; 6 Department of Pathology, HUSLAB and University of Helsinki, Finland; 7 Institut de Neurobiologie de la Méditerranée INMED UMR901, Marseille, France; 8 Department of Medical and Clinical Genetics, University of Helsinki, Finland Background: Charcot-Marie-Tooth neuropathy (CMT) is a heterogeneous disorder that affects 1:2500 people. ITPR3 encodes type 3 inositol 1,4,5-trisphosphate receptor (IP3R3), one of three such receptors in humans together with IP3R1 and IP3R2. IP3R3 is localized to ER-mitochondria contact sites where it facilitates movement of Ca2+ between the organelles. Here we studied the causative role of ITPR3 variants in patients with CMT and the role of IP3 receptors in stem cells. Methods: We used whole exome sequencing to identify disease-causing variants in four affected individuals with CMT in an autosomal dominant family. Skin fibroblasts from two affected individuals were analyzed by Western blotting, quantitative reverse transcription PCR and Ca2++ imaging. Knockouts of IP3 receptors in induced pluripotent stem cells (iPSC) were generated with CRISPR-Cas9. Results: Affected individuals had onset of symmetrical neuropathy with demyelinating features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. Altered Ca2+ transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant negative effect on IP3R3 function. For further analysis of IP3 receptor function, we generated iPSC-knockouts of the three receptors. Conclusions: With the genetic and functional evidence of our study, we conclude that ITPR3 is a new disease gene for Charcot-Marie-Tooth disease. Our results suggest that abnormal calcium signaling contributes to degeneration of peripheral nerves. IP3R knockout iPSC cell models provide a tool for further characterization of the receptors.
POSTERS 14 Can a human see a single photon? Tiihonen, J. (1), Dovzhik, K. (2), Tavala, A. (3), Zeilinger, A. (3), Ala-Laurila, P. (1,2) 1 Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland 2 Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland 3 Institute for Quantum Optics and Quantum Information - Vienna, Austrian Academy of Sciences, Vienna, Austria The human visual system is surprisingly sensitive to dim light stimuli. Classical studies in the 20th century quantified this notion by showing that we can reliably detect as few as 5 to 10 absorbed photons. This result consequently lead to the question whether humans could see just a single photon. However, the inherent photon variability of conventional light sources restricted the possibility to answer this question. Now, recent advances in quantum optics have re-ignited keen interest in this question, as newly introduced single-photon sources have reduced photon variability when compared to conventional light sources. Nonetheless, a prerequisite for using these single-photon sources is that the reduced variability can also be seen in biological responses. However, this prerequisite has not been tested in a rigorous way. Here, we now show for the first time that this prerequisite fails due to the losses of single-photon signals in the retina. Consequently, the reduced variability in biological responses can not be detected on a biologically relevant time scale and humans can basically never see a single photon.
POSTERS 15 Decline of Broad Ectodermal Pluripotency Leads to Neural Crest Formation Ceren Pajanoja (1,2),Laura Kerosuo (1,2) 1 Department of Biochemistry and Developmental Biology, Faculty of Medicine, Medicum, University of Helsinki, Helsinki, Finland 2 Neural Crest Development and Disease Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA Neural crest (NC) is an embryonic stem cell population that forms the craniofacial skeleton, peripheral nervous system and cells of the hormonal regulatory system. Despite its ectodermal origin, some NC derivatives show features of mesodermal or endodermally derived cells, which has puzzled researchers for decades and suggests the NC has an exceptionally high stem cell potential. The molecular mechanisms of how this stemness is acquired during early ectodermal development are not known.To uncover the process we performed Multiplex Spatial Transcriptomics (MST) at single cell level on chick embryo midbrain samples from multiple developmental stages. Surprisingly, our results show that the entire ectoderm at the neural fold stage, thus long after gastrulation, contains many undecided cells that could still become any of the ectodermal cell types (NC, central nervous system or epidermis), and which co-express the pluripotency factors. This contradicts previous assumptions of fully committed ectodermal domains at this stage. By the neural tube closure stage the NC domain has the highest expression of Nanog, which we think is linked to the broad stem cell potential maintained in the NC.Additionally, our bulk RNAseq from 12 consecutive stages from gastrula to NC migration show a consistent maintenance of pluripotency in the NC. Combined, we propose NC gains its high stemness by a process of gradual rather than abrupt decline of pluripotency in the ectoderm post gastrulation.
POSTERS 16 Effect of the Src inhibitory connexin43 region on lung cancer stem cells. Cerveró-García, P., García-Vicente,L., Tabernero, A. Universidad de Salamanca, Departamento de Bioquímica y Biología Molecular- Instituto de Neurociencias de Castilla y León INCyL, Salamanca, Spain; and Instituto de Investigación Biomédica de Salamanca IBSAL, Área de Neurociencias, Salamanca, Spain Connexin43 (Cx43) is a gap junction forming protein. Multiple studies have shown that Cx43 is related to cancer pathogenesis. Cx43 can suppress cancer cell growth through a mechanism mediated by its intracellular C terminus. Previous results indicate that Cx43 performs anti-tumourigenic effects in glioma cells by inhibiting the activity of c-Src oncoprotein. Based on this mechanism, a cell penetrating peptide was designed (Tat- Cx43266-283), which preserves the capacity of inhibiting Src on different in vitro and in vivo models of glioma. Src is a relevant oncogene, involved in numerous signaling pathways related to different cancer types, including lung cancer and lung cancer brain metastasis. Consequently, we asked whether the designed Src inhibitory peptide could impair brain metastasis as shown in primary brain tumours. To do so, we first analysed the effect on lung cancer stem cells. Using the human lung cancer cell line A549, we obtained a stem cell subpopulation from differentiated A549 cells. We carried out cell survival and protein expression assays at different times after the treatment with Tat-Cx43266-283 in differentiated and stem subpopulations of this cell line. We show the effects of Tat- Cx43266-283 on the expression of Cx43 and other Cx isoforms, on stem cell markers and on Src activity.These results aim us to explore the effect of the Src inhibitory peptide on lung brain metastasis models to address Tat-Cx43266-283 effects within the brain microenvironment.
POSTERS 17 Effect of TAT-Cx43266-283 on the expression and localization of Connexin43 Flores-Hernández, R., Talaverón, R. García-Vicente, L., Álvarez-Vázquez, A., Medina, J.M., Tabernero, A. Departamento de Bioquímica y Biología Molecular, Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Salamanca, Spain Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain Gliomas are the most common and aggressive primary brain tumors. Glioblastoma, its most malignant grade, are composed by a heterogeneous population of cells, including some called glioma stem cells (GSCs). These cells are highly tumorigenic and resistant to standard therapies. Connexin43 (Cx43) is an integral membrane protein, which in the brain is mainly found forming gap junctions in astrocytes. In addition, Cx43 forms hemichannels that release paracrine signals, and possesses channel-independent functions, including intracellular interaction with signalling molecules, such as the oncoprotein c-Src. Importantly, Cx43 inhibits c-Src activity by recruiting c-Src and its inhibitors. Based on this property, we developed a cell-penetrating peptide containing the region of Cx43 that interacts with c-Src (TAT-Cx43266-283). TAT-Cx43266-283 inhibits c-Src activity, reducing the growth and invasion of glioma cells without affecting neurons and astrocytes in several preclinical glioma models. In this study we addressed the effect of TAT-Cx43266-283 on Cx43 in glioma cells and the tumor microenvironment in a murine glioma model. To do so, Gl261-GSCs were intracranially injected in C57BL/6 mice. For the treated group, TAT- Cx43266-28 was coinjected with Gl261-GSCs and IP administered twice a week. We first analyzed different immunohistochemical methods. Then, we studied the effect of TAT- Cx43266-283 on the expression and localization of Cx43 in glioma cells and astrocytes.
POSTERS 18 Effect of the peptide TAT-Cx43266-283 on neural stem cells with EGFR alteration Álvarez-Vázquez, A. (1), Segura-Collar, B. (2), Sánchez-Gómez, P. (2), Tabernero, A. (1) 1 Instituto de Neurociencias de Castilla y León (INCyL), University of Salamanca, Salamanca, Spain 2 3 Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain Glioblastomas are one of the most malignant tumours worldwide. Among the causes of such malignancy is a subpopulation of tumour cells with stem cell properties known as Glioma Stem Cells (GSCs). These cells are resistant to standard treatments, such as temozolomide. Several studies have proposed Neural Stem Cells (NSCs) from the subventricular zone (SVZ) as a possible origin for GSCs. The transition of NSCs to GSCs frequently concurs with epidermal growth factor receptor (EGFR) alterations. Our group designed a cell penetrating peptide based on connexin43 (TAT-Cx43 266-283 ) that inhibits the activity of the oncoprotein c-Src and therefore targets GSCs, increasing survival rates in glioma-bearing mice. Because Src is involved in EGFR signaling, we explored the effect of TAT-Cx43 266-283 in the transition of NSCs to GSCs. For this purpose, we analysed the cell growth of SVZ NSCs (Control-NSCs), NSCs with EGFR amplification (EGFRwt-NSCs) and NSCs with the mutant EGFRvIII (EGFRvIII-NSCs). Our results show that TAT-Cx43 266-283 specifically inhibited the growth of EGFRwt-NSCs and EGFRvIII-NSCs, without significant effects in Control-NSCs. Importantly, we found that temozolomide and other control peptides did not affect the cell growth of any of these NSCs. EGFR activity was analyzed by Western blot and our preliminary results show a reduction in the activity of EGFR, EGFRvIII and Src. These results stress the relevance of TAT-Cx43 266-283 as a future therapy against glioblastoma.
POSTERS 19 Molecular migraine treatment via inhibition of endoCBs-hydrolyzing enzymes Della Pietra A., Giniatullin R., Savinainen J.R. A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; and Laboratory of Neurobiology, Kazan Federal University, Kazan, 420008, Russia; and Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland In migraine pain, cannabis has a promising analgesic action which, however, is associated with side psychotropic effects. To overcome these adverse effects of exogenous cannabinoids, we propose migraine pain relief via activation of the endogenous cannabinoid system (ECS) by inhibiting enzymes degrading endocannabinoids. To provide a functional platform for such purpose in the peripheral and central parts of the rat nociceptive system relevant to migraine, we measured by activity-based protein profiling (ABPP) the activity of the main endocannabinoid-hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). We found that in trigeminal ganglia, the MAGL activity was 9-fold higher than that of FAAH. MAGL activity exceeded FAAH activity also in DRG, spinal cord and brainstem. However, activities of MAGL and FAAH were comparably high in cerebellum and cerebral cortex implicated in migraine aura. MAGL and FAAH activities were identified and blocked by the selective and potent inhibitors JJKK- 048/KML29 and JZP327A, respectively. The high MAGL activity in trigeminal ganglia implicated in generation of nociceptive signals suggest this part of ECS as a priority target for blocking peripheral mechanisms of migraine pain. In the CNS, both MAGL and FAAH represent potential targets for attenuation of migraine-related enhanced cortical excitability and pain transmission.
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